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Kinetic analysis of 3'-deoxy-3'-fluorothymidine PET studies: validation studies in patients with lung cancer.

UNLABELLED: Assessing cellular proliferation provides a direct method to measure the in vivo growth of cancer. We evaluated the application of a model of 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) kinetics described in a companion report to the analysis of FLT PET image data in lung cancer patients. Compartmental model analysis was performed to estimate the overall flux constants (K(FLT)) for FLT phosphorylation in tumor, bone marrow, and muscle. Estimates of flux were compared with an in vitro assay of proliferation (Ki-67) applied to tissue derived from surgical resection. Compartmental modeling results were compared with simple model-independent methods of estimating FLT uptake. METHODS: Seventeen patients with 18 tumor sites underwent up to 2 h of dynamic PET with blood sampling. Metabolite analysis of plasma samples corrected the total blood activity for labeled metabolites and provided the FLT model input function. A 2-compartment, 4-parameter model (4P) was tested and compared with a 2-compartment, 3-parameter (3P) model for estimating K(FLT). RESULTS: Bone marrow, a proliferative normal tissue, had the highest values of K(FLT), whereas muscle, a nonproliferating tissue, showed the lowest values. The K(FLT) for tumors estimated by compartmental analysis had a fair correlation with estimates by modified graphical analysis (r = 0.86) and a poorer correlation with the average standardized uptake value (r = 0.62) in tumor. Estimates of K(FLT) derived from 60 min of dynamic PET data using the 3P model underestimated K(FLT) compared with 90 or 120 min of dynamic data analyzed using the 4P model. Comparison of flux estimates with an independent measure of cellular proliferation showed that K(FLT) was highly correlated with Ki-67 (Spearman rho = 0.92, P < 0.001). Ignoring the metabolites of FLT in blood underestimated K(FLT) by as much as 47%. CONCLUSION: Compartmental analysis of FLT PET image data yielded robust estimates of K(FLT) that correlated with in vitro measures of tumor proliferation. This method can be applied generally to other imaging studies of different cancers after validation of parameter error. Tumor loss of phosphorylated FLT nucleotides (k(4)) is notable and leads to errors when FLT uptake is evaluated using model-independent approaches that ignore k(4), such as graphical analysis or the SUV.

Algorithms↗

Kinetic analysis of 2-[11C]thymidine PET imaging studies: validation studies.

UNLABELLED: 2-[11C]thymidine has been tested as a PET tracer of cellular proliferation. We have previously described a model of thymidine and labeled metabolite kinetics for use in quantifying the flux of thymidine into DNA as a measure of tumor proliferation. We describe here the results of studies to validate some of the model's assumptions and to test the model's ability to predict the time course of tracer incorporation into DNA in tumors. METHODS: Three sets of studies were conducted: (a) The uptake of tracers in proliferative tissues of normal mice was measured early after injection to assess the relative delivery of thymidine and metabolites of thymidine catabolism (thymine and CO2) and calculate relative blood-tissue transfer rates (relative K1s). (b) By using sequential injections of [11C]thymidine and [11C]thymine in normal human volunteers, the kinetics of the first labeled metabolite were measured to determine whether it was trapped in proliferating tissue such as the bone marrow. (c) In a multitumor rat model, 2-[14C]thymidine injection, tumor sampling and quantitative DNA extraction were performed to measure the time course of label uptake into DNA for comparison with model predictions. RESULTS: Studies in mice showed consistent relative delivery of thymidine and metabolites in somatic tissue but, as expected, showed reduced delivery of thymidine and thymine in the normal brain compared to CO2. Thymine studies in volunteers showed only minimal trapping of label in bone marrow in comparison to thymidine. This quantity of trapping could be explained by a small amount of fixation of labeled CO2 in tissue, a process that is included as part of the model. Uptake experiments in rats showed early incorporation of label into DNA, and the model was able to fit the time course of uptake. CONCLUSION: These initial studies support the assumptions of the compartmental model and demonstrate its ability to quantify thymidine flux into DNA by using 2-[11C]thymidine and PET. Results suggest that further work will be necessary to investigate the effects of tumor heterogeneity and to compare PET measures of tumor proliferation to in vitro measures of proliferation and to clinical tumor behavior in patients undergoing therapy.

Animals↗

Cost-efficient design of a diet validation study.

Validation studies of food frequency questionnaires (FFQs) describe the extent to which the FFQ reflects true diet and the relation between measured and true diet (calibration). Calibration data can be used to estimate the relation between disease and diet that would have been observed in the absence of error due to the FFQ. In this paper, the authors consider the optimal design of a validation study when the goal is precise calibration of an FFQ. The authors posed the following question: Under the constraint of a fixed total cost for a validation study, what is the optimal choice of number of subjects (n) and number of days (m) of diet records (or 24-hour recalls) per subject? The optimal n and m were found to depend upon 1) the ratio between the costs of the initial and subsequent 1-day diet records and 2) the ratio of the variance in day-to-day nutrient intake to the variance in true diet for a fixed FFQ value. Data for the two ratios and optimal values of n and m are given under a variety of realistic scenarios. The authors conclude that in most settings the optimal study design will rarely require more than four or five 1-day diet records per subject.

Adult↗

Assessment of radiofrequency exposure from cellular telephone daily use in an epidemiological study: German Validation study of the international case-control study of cancers of the brain--INTERPHONE-Study.

OBJECTIVE: The objective of the study is to validate self-reported cellular phone use information by comparing it with the cumulative emitted power and duration of calls measured by software-modified cellular phones (SMP). The information was obtained using a questionnaire developed for the international case-control study on the risk of the use of mobile phones in tumours of the brain or salivary gland (INTERPHONE-study). METHOD: The study was conducted in Bielefeld, Germany. Volunteers were asked to use SMPs instead of their own cellular phones for a period of 1 month. The SMP recorded the power emitted by the mobile phone handset during each base station contact. Information on cellular phone use for the same time period from traffic records of the network providers and from face-to-face interviews with the participants 3 months after the SMP use was assessed. Pearson's correlation coefficients and linear regression models were used to analyse the association between information from the interview and from the SMP. RESULTS: In total, 1757 personal mobile phone calls were recorded for 45 persons by SMP and traffic records. The correlation between the self-reported information about the number and the duration of calls with the cumulative power of calls was 0.50 (P<0.01) and 0.48 (P<0.01), respectively. Almost 23% of the variance of the cumulative power was explained by either the number or the cumulative duration of calls. After inclusion of possible confounding factors in the regression model, the variance increased to 26%. Minor confounding factors were "network provider", "contract form", and "cellular phone model". DISCUSSION: The number of calls alone is a sufficient parameter to estimate the cumulative power emitted by the handset of a cellular telephone. The cumulative power emitted by these phones is only associated with number of calls but not with possible confounding factors. Using the mobile phone while driving, mainly in cities, or mainly in rural areas is not associated with the recorded cumulative power in the SMP.

Automation↗

Is there really a heterosexual AIDS epidemic in the United States? Findings from a multisite validation study, 1992-1995. Mode of Transmission Validation Study Group.

The objective of this study was to verify the mode of exposure to the human immunodeficiency virus (HIV) among cases who obtained acquired immunodeficiency syndrome (AIDS) through heterosexual contact and to determine the proportion of cases initially reported with no risk but whose exposure may have been heterosexual. Adults aged > or = 13 years with AIDS, diagnosed from 1992 through 1995 with heterosexual risk or no risk at six US study sites (Alabama, California, Florida, New Jersey, New York City, and Texas), were eligible. Heterosexual risk was validated in 82% (1,610/1,952) of the heterosexual cases. Men were more likely than women to have a risk other than heterosexual (24% vs. 13%, chi2 p < 0.01). An HIV risk was identified for 351 (55%) of those cases with no risk, and men were more likely than women to remain without risk (48% vs. 38%, chi2 P = 0.02). Of the 415 men with no risk, 215 (52%) were reclassified: 94 (44%) were men who had sex with men, 61 (28%) were injection drug users, 48 (22%) had a heterosexual risk, and 12 (6%) had other exposures. Of the 219 women with no risk, 136 (62%) were reclassified: 82 (60%) had a heterosexual risk, 47 (35%) were injection drug users, and 6 (4%) had infection associated with transfusion. In conclusion, most cases reported with heterosexually acquired AIDS had valid heterosexual risk exposures.

Acquired Immunodeficiency Syndrome↗

Measurement of cortical thickness using an automated 3-D algorithm: a validation study.

A validation study was conducted to assess the accuracy of the algorithm developed by MacDonald et al. (1999) for measuring cortical thickness. This algorithm automatically determines the cortical thickness by 3-D extraction of the inner and outer surfaces of the cerebral cortex from an MRI scan. A manual method of tagging the grey-csf and grey-white interface was used on 20 regions (10 cortical areas found in each hemisphere) in 40 MRIs of the brain to validate the algorithm. The regions were chosen throughout the cortex to get broad assessment of the algorithm's performance. Accuracy was determined by an anatomist tagging the csf-grey and grey-white borders of selected gyri and by allowing the algorithm to determine the csf-grey and grey-white borders and the corresponding cortical thickness of the same region. Results from the manual and automatic methods were statistically compared using overall ANOVA and paired t tests for each region. The manual and automatic methods were in agreement for all but 4 of the 20 regions tested. The four regions where there were significant differences between the two methods were the insula left and right, the right cuneus, and the right parahippocampus. We conclude that the automatic algorithm is valid for most of the cortex and provides a viable alternative to manual methods of determining cortical thickness in vivo. However, caution should be taken when measuring the regions mentioned previously where the results of the algorithm can be biased by surrounding grey structures.

Adult↗

Circumplex Model VII: validation studies and FACES III.

This paper reviews some of the recent empirical studies validating the Circumplex Model and describes the newly developed self-report measure, FACES III. Studies testing hypotheses derived from the Circumplex Model regarding the three dimensions of cohesion, change, and communication are reviewed. Case illustrations using FACES III and the Clinical Rating Scale are presented. These two assessment tools can be used for making a diagnosis of family functioning and for assessing changes over the course of treatment. This paper reflects the continuing attempt to develop further the Circumplex Model and to bridge more adequately research, theory, and practice.

Adaptation, Psychological↗

A validation study on the reproducibility of transcranial Doppler velocimetry.

The transcranial Doppler method for the measurement of intracranial arterial blood flow velocity is a useful noninvasive technique with a number of applications. The present study validated the reproducibility of this method for repeated measurements of flow velocity in the middle cerebral and basilar arteries. Fifteen healthy volunteers were studied. Measurements were made twice by one examiner and once by another in a single day and again by the first examiner on another day. The reproducibility was evaluated by calculating the correlation coefficient (r) and the coefficient of variation (CV) of the difference between the values obtained from each pair of measurements. Although depending on the examiner, the time interval between the examinations and the vessels studied some differences were noted in the reproducibility, both the r (0.69-0.95) and CV (6.7%-19.5%) values in the whole study were good enough to warrant the applicability of this method for the repeated measurements of the intracranial arterial blood flow velocity in future studies.

Cerebral Arteries↗

Lean body mass estimation by bioelectrical impedance analysis: a four-site cross-validation study.

This study validated further the bioelectrical impedance analysis (BIA) method for body composition estimation. At four laboratories densitometrically-determined lean body mass (LBMd) was compared with BIA in 1567 adults (1069 men, 498 women) aged 17-62 y and with 3-56% body fat. Equations for predicting LBMd from resistance measured by BIA, height, weight, and age were obtained for the men and women. Application of each equation to the data from the other labs yielded small reductions in R values and small increases in SEEs. Some regression coefficients differed among labs but these differences were eliminated after adjustment for differences among labs in the subjects' body fatness. All data were pooled to derive fatness-specific equations for predicting LBMd: the resulting R values ranged from 0.907 to 0.952 with SEEs of 1.97-3.03 kg. These results confirm the validity of BIA and indicate that the precision of predicting LBM from impedance can be enhanced by sex- and fatness-specific equations.

Adolescent↗

Quantitative biopsy pathology for the prediction of pathologically organ-confined prostate carcinoma: a multiinstitutional validation study.

BACKGROUND: Quantitative biopsy pathology with prostate specific antigen significantly improves the prediction of pathologic stage in patients with clinically localized prostate carcinoma (PCa). The authors recently reported a computational model for predicting patient specific likelihood of organ confinement of PCa using biopsy pathology and clinical data. The current study validates the initial models and presents an new, improved tool for clinical decision making. METHODS: The authors assessed 10 biopsy pathologic parameters and 2 clinical parameters using data from two institutions. Of 1287 patients, 798 men had pathologically organ confined (OC) PCa, 282 men had nonorgan-confined disease with capsular penetration (NOC-CP) only, and 207 men showed seminal vesicle or lymph node invasion (NOC-AD) after undergoing pelvic lymphadenectomy and radical prostatectomy. Patient input data were evaluated by ordinal logistic (OLOGIT) and neural network (NN) models; and the likelihood of developing OC, NOC-CP, or NOC-AD disease was calculated for the combined and separate data sets and was compared with the results from original presentation. In addition, a new two-output model was constructed (OC/NOC-CP vs. NOC-AD). RESULTS: The three-output OLOGIT and NN models predicted OC disease with 95.0% and 98.6% accuracy, respectively, for the combined data set and with 93.0% and 98.6% accuracy, respectively, on subset analysis. The combined accuracy for predicting OC, NOC-CP, and NOC-AD disease in the entire validation set was 66.7% for OLOGIT model and 66.0% for the NN model. The two-output OLOGIT and NN models correctly predicted 94.9% and 100.0% of all OC/NOC-CP disease, respectively. CONCLUSIONS: Both computation models predicted OC PCa with an accuracy of 93.0-98.6% when they were validated with two different data sets. The OLOGIT and NN-based, two-output model permitted an appropriate treatment decision for 85.2-90.2% of patients. These data support the use of quantitative pathology and clinical data-based decision modeling to manage patients with clinically localized PCa.

Biopsy↗

Screening for asthma by population ranking: a validation study.

PURPOSE: A neural network system was previously developed to rank a population in order of asthma probability based on responses to a postal questionnaire. Respondents ranked higher than a percentage point screening threshold are offered clinical review. The present study validates this system in a new population that had not been involved in system development. METHODS: The system was used to rank respondents to a community survey and to predict positive predictive value (PPV) for percentage point thresholds between the top 1% and 10% of the ranking. Respondents in the top 10% were invited for clinical review. Review information and expert opinion was used to designate respondents as clinically "asthmatic" or "non-asthmatic." PPV prediction for each threshold was compared with clinical status of respondents. RESULTS: As the threshold increased from 1% to 10%, the additional yield of clinical asthmatics decreased, indicating a ranking in asthma probability order (all 7 in the top 1% were clinical asthmatics compared with 91% of the top 5% and 83% of the top 10%). Percentages of clinical asthmatics were generally slightly higher than system PPV predictions. CONCLUSIONS: The system ranked the population in asthma probability order and estimated PPV conservatively, enabling health-care providers to predict resource implications of a screening program.

Asthma↗

Transcranial Doppler measurement of middle cerebral artery blood flow velocity: a validation study.

Measurement of intracranial arterial blood flow velocity is a new technique with potentially a number of very useful applications. This study validates the technique by comparing it to cerebral blood flow (CBF) measured using intravenous Xenon133 and extracranial clearance recording. We have measured the middle cerebral artery (MCA) blood flow velocity in 17 symptomatic patients with the EME TC 264 transcranial Doppler velocimeter and compared these measurements to the ipsilateral hemispheric cerebral blood flow measured with an intravenous Xenon133 technique (Novo Cerebrograph 10A). Measurements were made at rest and during hypercapnia. The absolute measurement of MCA velocity and hemispheric CBF showed a poor correlation (r = 0.424, p less than 0.01) due to wide between-patient variations at rest but the blood flow response to hypercapnia, expressed as a reactivity index, showed a good correlation (r = 0.849, p less than 0.001). Thus changes in MCA velocity reliably correlate with changes in cerebral blood flow but the absolute velocity cannot be used as an indicator of CBF.

Adult↗

The Ego Impairment Index and schizophrenia: a validation study.

This study is an extension of our work on a new scale, the Ego Impairment Index (EII; Perry & Viglione, 1991). The index is theoretically based on Beres's (1956) model of ego assessment and was empirically developed on a sample of melancholic, depressed outpatients, diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders (3rd ed. [DSM-III]; American Psychiatric Association, 1980). The EII is derived from the Rorschach Inkblot Test and offers a single composite score of ego impairment. This study validates the use of the EII with a heterogeneous sample of schizophrenic patients. In support of the trait-like characteristics of the scale, the EII continues to be expressed as a single factor, with a correlation of .98 when comparing the original factor derived from a melancholic population with this sample of schizophrenic patients. Significant correlations were also found between the EII and other clinical indices, including the Magical Ideation Scale, the Schizophrenia Index, and the Minnesota Multiphasic Personality Inventory (MMPI). Finally, the EII was found to differentiate between a paranoid subgroup and a mixed undifferentiated/disorganized subgroup who theoretically have more ego impairment. These results offer support for the use of the EII as an empirical means of quantitatively and qualitatively assessing thought disorder within a theoretical framework. Further research is needed to understand the application of the EII across different diagnostic groups and its relationship to other indices of psychological disturbance.

Adult↗

The dose-to-mother method to measure milk intake in infants by deuterium dilution: a validation study.

A validation study of the dose-to-mother deuterium dilution method to measure breast-milk intake has been carried out on ten infants from a Nutrition Recovery Centre in Santiago, Chile. Formula milk labelled with exponentially decreasing doses of deuterium oxide represented milk from a 'pseudo mother' of these exclusively bottle-fed infants. Unlabelled formula represented milk from other sources. Deuterium levels in the infants' body water were measured on saliva samples by mass spectroscopy. The data were fitted in a two-compartment steady-state model of the mother-child system to estimate the flow of labelled water from the 'mother' to the infant and the 'mother' and infant's water elimination constants. A dose-to-child experiment was also carried out on each infant to determine the deuterium dilution space and total daily water intake. Total and labelled water flows from deuterium dilution were used to calculate total, labelled and unlabelled formula milk intakes which were compared to the same quantities measured by bottle weighing. Water elimination constants calculated from the dose-to-mother experiments underestimated by 17 per cent the initially set mother constant and overestimated by 21 per cent the infant constants calculated from the dose-to-child experiments. Rate constants, however, have little effect on the estimated water flows so that there was good agreement between values from deuterium dilution and from direct weighing. Mean (SD) total formula, labelled formula and unlabelled formula intakes were 865 (129) g/d, 417 (74) g/d and 448 (106) g/d, respectively, when measured by deuterium dilution, compared with 856 (116) g/d, 414 (71) g/d and 441 (68) g/d when measured by direct weighing. The mean per cent differences were 1.1 per cent, 0.7 per cent and 1.6 per cent and the mean absolute differences for individuals, 4.3 (1.9) per cent, 4.8 (3.1) per cent and 9.7 (6.6) per cent, respectively.

Deuterium↗

Relative validity of a food frequency questionnaire among tin miners in China: 1992/93 and 1995/96 diet validation studies.

OBJECTIVE: Diet validation research was conducted to compare the respondents' reporting of dietary intake in a food frequency questionnaire (FFQ) with intake reported in food recalls. Because the population received annual salary increments that could modify food intake, diet validation studies (DVSs) were conducted during two time intervals. DESIGN: A 99-item FFQ was administered by an interviewer twice in a 1-year interval, and responses to each FFQ item were compared with 28 days of interviewer-administered food recalls that were collected in four 1-week intervals during each season of 1992/93. The second validation study in 1995/96 had a similar design to the earlier one. SETTING: A prospective cohort study of lung cancer among tin miners in China was initiated in 1992, with dietary and other risk factors updated annually. SUBJECTS: Among a cohort of high risk tin miners for lung cancer, two different samples (n = 141 in 1992/93, and n = 113 in 1995/96) for each diet validation study were randomly selected from four mine units, that were representative of all worker units. RESULTS: Miners reported a significantly higher average frequency of intake of foods in the food recalls than the FFQ, with few exceptions. Deattenuated Pearson correlation coefficients of the frequency of food intake between the FFQ and food recalls were in the range of -0.40 to 0.72 in both studies, with higher positive correlations for beverages and cereal staples than for animal protein sources, vegetables, fruits and legumes. The percentage of individuals with exact agreement in the extreme quartiles of intake in the food recalls and FFQ ranged from 0 to 100% in both studies. CONCLUSIONS: Among Chinese miners, the range in correlations between the food recalls and the FFQ were due to: (i) market availability of foods during the food recall weeks compared to their annual reported intake in the FFQ; (ii) cultural perception of time; and (iii) differences in how the intake of mixed dishes and their multi-ingredient foods were reported in the recalls vs. the FFQ. The range in the percentage of agreement in the same quartiles and the changes in food intake over time may have implications for the analysis of the diet-disease relationship in this cohort.

Analysis of Variance↗

Iontophoretic R-apomorphine delivery in combination with surfactant pretreatment: in vitro validation studies.

To validate the efficacy and controllability of a newly developed transdermal delivery system for R-apomorphine in combination with the surfactant pretreatment, iontophoresis was performed in three-chamber continuous-flow-through diffusion cells in vitro. The transdermal iontophoretic transport of R-apomorphine was examined with both human SC and freshly dermatomed human skin, at room temperature and at 32 degrees C. Furthermore, the relationship between current density and iontophoretic flux was investigated. By increasing the temperature from 22 to 32 degrees C, the iontophoretic transport rate of R-apomorphine in human SC was increased 1.9-fold. Also the iontophoretic flux increased linearly with the increase in the current density from 100 to 500 microA/cm(2). When using dermatomed human skin instead of SC, the iontophoretic flux at a current density of 500 microA/cm(2) was decreased from 362+/-45 to 259+/-30 nmol/cm(2)h, and the corresponding lag time was prolonged from 0.8 to 2.8h. In conclusion, the combination of non-occlusive pretreatment with the surfactant formulation and iontophoresis has shown to substantially increase the transdermal transport rate of R-apomorphine. A linear relationship between current density and R-apomorphine flux indicates that the iontophoretic delivery combined with surfactant pretreatment allows a controlled and individualised administration of R-apomorphine.

Apomorphine↗

Communication Capacity Scale and Agitation Distress Scale to measure the severity of delirium in terminally ill cancer patients: a validation study.

Although valid measurement of the severity of terminal delirium is of great importance in palliative care settings, existing instruments have considerable limitations. In order to quantify patients' communication capacity and agitated behaviour, two new operational observer-rating scales, the Communication Capacity Scale (Communication Scale) and Agitation Distress Scale (Agitation Scale), were validated. Thirty terminally ill cancer patients diagnosed with delirium were evaluated simultaneously by two palliative care physicians blinded to each other's coding using the Communication Scale and Agitation Scale. In addition, the Memorial Delirium Assessment Scale (MDAS), Delirium Rating Scale (DRS) and Sedation Scale were rated by one researcher. Both scales achieved high internal consistency and inter-rater reliability with Cronbach's alpha coefficients of 0.91 and 0.96, and Cohen's kappa values on each item of 0.72-1.00. The principal components analysis resulted in the emergence of only one component for each scale. The total score on the Communication Scale was highly associated with that of the MDAS (rho = 0.78), Sedation Scale (rho = 0.86), and cognitive items from the MDAS and DRS (rho = 0.83). The whole score on the Agitation Scale was significantly correlated with that of the DRS (rho = 0.61) and agitation items from the MDAS and DRS (rho = 0.61). In conclusion, the Communication Scale and Agitation Scale have acceptable reliability and validity to quantify patients' communication capacity and agitation symptoms of terminally ill cancer patients with delirium.

Adult↗